Rat study sug­gests Al­ler­gan's failed an­ti­de­pres­sant ra­pastinel may work as opi­oid ad­dic­tion treat­ment

Last month, when Al­ler­gan’s $AGN once-tout­ed pipeline star ra­pastinel crashed and burned a slate of piv­otal de­pres­sion stud­ies, it looked like the ex­per­i­men­tal mod­u­la­tor of the NM­DA re­cep­tor would be shroud­ed in a cloak of in­vis­i­bil­i­ty — but re­searchers may have found a way to res­cue the ex­per­i­men­tal drug by re­pur­pos­ing it as a treat­ment for opi­oid de­pen­dence.

Ju­lia Fer­rante

In the Unit­ed States, the cri­sis of opi­oid abuse, mis­use and over­dose — from pre­scrip­tion painkillers, hero­in, and syn­thet­ic opi­oids such as fen­tanyl — has reached epi­dem­ic pro­por­tions, caus­ing 130 deaths every day, ac­cord­ing to NIH es­ti­mates. Once in with­draw­al, ad­dicts are left to cope with a myr­i­ad of symp­toms in­clud­ing anx­i­ety, ag­i­ta­tion, sleep prob­lems, mus­cle aches, run­ny nose, sweat­ing, nau­sea, vom­it­ing, di­ar­rhea and opi­oid crav­ings.

In or­der to man­age these of­ten de­bil­i­tat­ing symp­toms, with­draw­al is man­aged by sub­sti­tu­tion with a less pow­er­ful opi­oid, fol­lowed by grad­ual re­duc­tion or tran­si­tion to main­te­nance ther­a­py with FDA-ap­proved med­ica­tion-as­sist­ed treat­ment (MAT) drugs such as methadone, buprenor­phine or nal­trex­one, which can have un­pleas­ant and some­times dan­ger­ous side ef­fects and of­ten must be used for months to avoid re­lapse. Al­though the process of ta­per­ing opi­oid con­sump­tion and us­ing MAT to treat opi­oid ad­dic­tion is stan­dard-of-care, it sus­tains the brain changes that re­sult in ad­dic­tion in the first place, which can lead to re­lapse be­fore treat­ment is com­plet­ed, ac­cord­ing to re­searchers who eval­u­at­ed the use of ra­pastinel in opi­oid de­pen­dence.

The tri­al in rats test­ed the use of ra­pastinel ver­sus ke­t­a­mine — a com­mon­ly-used cat tran­quil­iz­er and par­ty drug known as Spe­cial K or Kit Kat — which has been pro­posed as an al­ter­na­tive, non-opi­oid treat­ment for opi­oid with­draw­al, but it has the po­ten­tial for abuse, in­duces a trance-like state and can cause hal­lu­ci­na­tions. In fact, J&J’s $JNJ ke­t­a­mine-based de­pres­sion drug Spra­va­to has al­ready won FDA ap­proval. Ra­pastinel binds to the same re­cep­tor as ke­t­a­mine but at a dif­fer­ent site, where it con­fers a milder ef­fect.

Cyn­thia Kuhn

The sci­en­tists first in­duced opi­oid de­pen­dence in male and fe­male ado­les­cent (be­tween 28 and 30 days old) Sprague-Daw­ley rats by in­ject­ing them with mor­phine in in­creas­ing dos­es twice a day for five days. On day six, rats were in­ject­ed with nalox­one and with­draw­al signs were quan­ti­fied. The rats were then giv­en ei­ther ke­t­a­mine in­jec­tions twice dai­ly (n=12), ra­pastinel in­jec­tions every oth­er day (n=14), or saline in­jec­tions (n=24). On day nine, when the rats were giv­en nalox­one to mea­sure with­draw­al signs, ra­pastinel-treat­ed rats ex­hib­it­ed sig­nif­i­cant­ly few­er with­draw­al signs than those treat­ed with ke­t­a­mine.

The find­ings sug­gest that treat­ment with ra­pastinel in­duced safer with­draw­al, sans any se­ri­ous side ef­fects, dur­ing the crit­i­cal first days in the ef­fort to ab­stain from opi­oid use — and the sci­en­tists hy­poth­e­sized this would lead to a de­creased risk of opi­oid re­lapse.

“Ra­pastinel re­search for opi­oid de­pen­den­cy is cur­rent­ly on­ly be­ing done in ro­dents, but if the drug con­tin­ues to have suc­cess­ful tri­als, it may en­ter clin­i­cal tri­als for use in hu­mans,” said Ju­lia Fer­rante, an un­der­grad­u­ate at Vil­lano­va Uni­ver­si­ty who con­duct­ed the re­search with Cyn­thia Kuhn, pro­fes­sor of phar­ma­col­o­gy and can­cer bi­ol­o­gy at Duke Uni­ver­si­ty.

The re­searchers are look­ing to keep test­ing ra­pastinel to in­ves­ti­gate its ef­fect on the mol­e­c­u­lar lev­el and to check whether it can re­duce the risk of re­lapse. The drug has a long way to go be­fore it cross­es the fin­ish line, but if ap­proved it would like­ly be ad­min­is­tered in­tra­venous­ly, pos­si­bly in an out­pa­tient set­ting, Fer­rante added.

De­vel­op­ment of the Next Gen­er­a­tion NKG2D CAR T-cell Man­u­fac­tur­ing Process

Celyad’s view on developing and delivering a CAR T-cell therapy with multi-tumor specificity combined with cell manufacturing success
Transitioning potential therapeutic assets from academia into the commercial environment is an exercise that is largely underappreciated by stakeholders, except for drug developers themselves. The promise of preclinical or early clinical results drives enthusiasm, but the pragmatic delivery of a therapy outside of small, local testing is most often a major challenge for drug developers especially, including among other things, the manufacturing challenges that surround the production of just-in-time and personalized autologous cell therapy products.

Roger Perlmutter, Merck

#ASH19: Here’s why Mer­ck is pay­ing $2.7B to­day to grab Ar­Qule and its next-gen BTK drug, lin­ing up Eli Lil­ly ri­val­ry

Just a few months after making a splash at the European Hematology Association scientific confab with an early snapshot of positive data for their BTK inhibitor ARQ 531, ArQule has won a $2.7 billion buyout deal from Merck.

Merck is scooping up a next-gen BTK drug — which is making a splash at ASH today — from ArQule in an M&A pact set at $20 a share $ARQL. That’s more than twice Friday’s $9.66 close. And Merck R&D chief Roger Perlmutter heralded a deal that nets “multiple clinical-stage oral kinase inhibitors.”

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Game on: Re­gen­eron's BC­MA bis­pe­cif­ic makes clin­i­cal da­ta de­but, kick­ing off mul­ti­ple myelo­ma matchup with Bris­tol-My­ers

As J&J attempts to jostle past Bristol-Myers Squibb and bluebird for a landmark approval of its anti-BCMA CAR-T — and while GlaxoSmithKline maps a quick path to the FDA riding on its own BCMA-targeting antibody-drug conjugates — the bispecifics are arriving on the scene to stake a claim for a market that could cross $10 billion per year.

The main rivalry in multiple myeloma is shaping up to be one between Regeneron and Bristol-Myers, which picked up a bispecific antibody to BCMA through its recently closed $74 billion takeover of Celgene. Both presented promising first-in-human data at the ASH 2019 meeting.

FDA lifts hold on Abeon­a's but­ter­fly dis­ease ther­a­py, paving way for piv­otal study

It’s been a difficult few years for gene and cell therapy startup Abeona Therapeutics. Its newly crowned chief Carsten Thiel was forced out last year following accusations of unspecified “personal misconduct,” and this September, the FDA imposed a clinical hold on its therapy for a form of “butterfly” disease. But things are beginning to perk up. On Monday, the company said the regulator had lifted its hold and the experimental therapy is now set to be evaluated in a late-stage study.

Paul Hudson. Sanofi

New Sanofi CEO Hud­son adds next-gen can­cer drug tech to the R&D quest, buy­ing Syn­thorx for $2.5B

When Paul Hudson lays out his R&D vision for Sanofi tomorrow, he will have a new slate of interleukin therapies and a synthetic biology platform to boast about.

The French pharma giant announced early Monday that it is snagging San Diego biotech Synthorx in a $2.5 billion deal. That marks an affordable bolt-on for Sanofi but a considerable return for Synthorx backers, including Avalon, RA Capital and OrbiMed: At $68 per share, the price represents a 172% premium to Friday’s closing.

Synthorx’s take on alternative IL-2 drugs for both cancer and autoimmune disorders — enabled by a synthetic DNA base pair pioneered by Scripps professor Floyd Romesberg — “fits perfectly” with the kind of innovation that he wants at Sanofi, Hudson said.

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Roche faces an­oth­er de­lay in strug­gle to nav­i­gate Spark deal past reg­u­la­tors — but this one is very short

Roche today issued the latest in a long string of delays of its $4.3 billion buyout of Philadelphia-based Spark Therapeutics. The delay comes as little surprise — it is their 10th in as many months — as their most recent delay was scheduled to expire before a key regulatory deadline.

But it is notable for its length: 6 days.

Previous extensions had moved the goalposts by about 3 weeks to a month, with the latest on November 22 expiring tomorrow. The new delay sets a deadline for next Monday, December 16, the same day by which the UK Competition and Markets Authority has to give its initial ruling on the deal. And they already reportedly have lined up an OK from the FTC staff – although that’s only one level of a multi-step process.

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KalVis­ta's di­a­bet­ic mac­u­lar ede­ma da­ta falls short — will Mer­ck walk away?

Merck’s 2017 bet on KalVista Pharmaceuticals may have soured, after the UK/US-based biotech’s lead drug failed a mid-stage study in patients with diabetic macular edema (DME).

Two doses of the intravitreal injection, KVD001, were tested against a placebo in a 129-patient trial. Patients who continued to experience significant inflammation and diminished visual acuity, despite anti-VEGF therapy, were recruited to the trial. Typically patients with DME — the most frequent cause of vision loss related to diabetes — are treated with anti-VEGF therapies such as Regeneron’s flagship Eylea or Roche’s Avastin and Lucentis.

UP­DAT­ED: Ob­sE­va makes case for best-in-class hor­mone sup­pres­sive ther­a­py in pos­i­tive uter­ine fi­broid study

About a month after the Swiss biotech disclosed a failed late-stage study in its IVF program, ObsEva on Monday unveiled positive pivotal data on its experimental treatment for heavy menstrual bleeding triggered by uterine fibroids.

ObsEva in-licensed the drug, linzagolix, from Japan’s Kissei Pharmaceutical in 2015. Two doses of the drug (100 mg and 200 mg) were tested against a placebo in the 535-patient Phase III study, dubbed PRIMROSE 2, in patients who were both on and off hormonal add-back therapy (ABT).

Ear­ly-stage can­cer biotech nails $85M C round; Flem­ming Orn­skov's Gal­der­ma scores 'break­through' sta­tus

→ Zentalis Pharmaceuticals just nabbed an $85 million round from a syndicate that includes Matrix Capital, Viking Global Investors, Redmile Group, Farallon Capital, Perceptive Advisors, Surveyor Capital and Eventide Asset Management. Their lead drug is ZN-c5, which is currently in Phase I/II trials. The biotech describes that drug as a “potential best-in-class oral Selective Estrogen Receptor Degrader for estrogen receptor-positive, HER2-negative (ER+/ HER2-) breast cancer.”